The beta-adrenergic receptor mediated modulation of myocardial performance, a major component of cardiovascular reserve function, declines with aging i health and in heart failure due to a variety of causes. While signal transduction mechanisms for the beta1AR stimulation have been intensively studied, little information exerts as to the specific mechanisms that coupl beta2AR stimulation to its cellular responses. It has been well established that both beta1- and beta2-adrenoceptor (AR) subtypes increase the activity of adenylyl cyclase via an interaction with Gs, raising the internal cAMP concentration. However, our initial studies of this project have demonstrated that while both beta1AR and beta2AR stimulation increase total cellular cAMP to a similar extent in rat ventricular myocytes, the effects of beta2AR stimulation on ICa, Cabeta2+ transient and contraction are largely dissociated from its effect to increase cAMP content. Furthermore, while the beta2-adrenergic agonist, zinterol, significantly increases ICa, Ca2+ transient and contraction amplitudes in dog cardiac cells, it has no effect on the cellular cAMP production. These results suggest that beta2AR might be coupled to signaling pathway(s) other than the Gsalpha-mediated activation of adenylyl cyclase. Pertussis toxin (PTX) is a useful tool to eliminate signal transduction via some Gi or Go proteins. Our subsequent studies have shown that pertussis toxin (PTX) pretreatment specifically potentiates the responses of rat heart cells to beta2AR stimulated increase in Ca2+ transient, contraction and Ca2+ current (ICa). In contrast, neithe the baseline ICa, Ca2+ transient or contraction in the absence of betaAR stimulation, nor the beta1AR-mediated augmentation of these parameters are significantly altered by PTX treatment. These results indicate that in the absence of PTX, substantial coupling occurs between beta2AR and a PTX- sensitive G-protein, exerting a negative feedback on the cellular responses to beta2AR stimulation. Thus, distinct betaR subtype actions reside, at least in part, in the different receptor-G protein interaction. The difference provides a potential therapeutic strategy to reverse, in part, the decline in cardiac reserve with aging and heart failure.